1. Field of the Invention
The present invention relates to methods for treatment of neurological injuries and neurodegenerative disorders. More particularly, in one aspect, the invention includes methods of use of the polypeptide GDF-1, or a fragment or derivative of GDF-1, or a nucleic acid encoding GDF-1, to treat a subject suffering from or susceptible to a neurological injury or neurodegenerative disease. The invention also provides methods for treatment of neurological injury and neurodegenerative disease with a combination of GDF-1 that comprise administration of a combination of GDF-1 and neurotrophin-3 (NT-3).
2. Background
Nerve cell death (degeneration) can cause potentially devastating and irreversible effects for an individual and may occur e.g. as a result of stroke, heart attack or other brain or spinal chord ischemia or trauma. Additionally, neurodegenerative disorders, such as Alzheimer's disease, Parkinson's disease, Huntington's disease, Amyotrophic Lateral Sclerosis, Down's Syndrome and Korsakoff's disease, involve nerve cell death (degeneration).
Therapies have been investigated to treat nerve cell degeneration and related disorders, e.g., by limiting the extent of nerve cell death that may otherwise occur to an individual as well as promoting repair, remodeling and reprogramming after stroke or other neuronal injury. See, e.g., F. Seil, Curr Opin Neuro, 10:49-51 (1997); N. L. Reddy et al., J Med Chem, 37:260-267 (1994); and WO 95/20950.
Certain growth factors have been reported to exhibit neuroprotective properties. In particular, nerve growth factor (NGF) has been evaluated in certain animal models of injury to or degeneration of nervous tissue. See, for example, G. Sinson et al., J. Neurosurg, 86(3):511-518 (1997); and G. Sinson et al., J Neurochem, 65(5):2209-2216 (1995). Osteogenic protein-1 (OP-1) has been evaluated in a rat model of cerebral hypoxia/ischemia for neuroprotective activity. G. Perides, Neurosci Lett, 1871):21-24 (1995). Glial cell line-derived neurotrophic factor (GDNF) was reported to exhibit trophic activity on certain populations of central neurons. Y. Wang et al., J Neurosci, 17(11):4341-4348 (1997). Small molecules, such as MK-801, also have been investigated as neuroprotective agents. See B. Meldrum, Cereb Brain Metab Rev, 2:27-57 (1990); D. Choi, Cereb Brain Metab Rev, 2:27-57 (1990).
However, no effective pharnacotherapies are in regular clinical use for ischemia-induced brain injury or other such injuries and disorders. See, for example, Y. Wang et al., supra; G. Sinson et al., J Neurochem, 65(5):2209 (1995).
It thus would be highly desirable to have new neuroprotective agents, particularly agents to limit the extent or otherwise treat nerve cell death (degeneration) that occur with stroke, heart attack or brain or spinal cord trauma, or to treat Alzheimer's disease, Parkinson's disease, Huntington's disease, Amyotrophic Lateral Sclerosis, Down's Syndrome and Korsakoffs disease. It also would be desirable to have agents that promote repair, remodeling or reprogramming after stroke or other neuronal injury.